Obesity, a common condition associated with many diseases is defined as a body fat content of greater than 30% in females and greater than 35% in males or a body mass index of greater than 30 for both men and women. While this definition is simple, the pathophysiology of obesity is both heterogeneous and complex. Recent studies have shown recessive major gene effects for obesity in randomly ascertained families. These findings now support the need to investigate specific subsets of obesity for the purpose of restricting genetic heterogeneity. Morbid obesity is one such subset, occurring in only 1-2 percent of the population. Although the genetic basis of this extreme overweight disorder is not understood, it is likely there are individual major genes responsible for morbid obesity in families. To advance this aim, we began a pilot study last year and identified families of 221 morbidly obese probands (1652 subjects) to obtain the height and weight of each family member. Morbid obesity was defined as 100 pounds or 100 percent over ideal weight. which represents a body mass index of approximately 42-45 or greater. Preliminary analyses revealed strong familial aggregation of morbid obesity, with 50 percent of the morbidly obese probands having one or more first degree relatives who were also morbidly obese. The familial aggregation was similar for early-onset and late-onset morbid obesity. There was evidence for increased risk in the offspring of morbidly obese parents compared to offspring of nonmorbidly obese parents (odds ratio of 2.3). Finally there was significant bimodality for body mass index in both males and females in these families. Using this subset of extreme obesity, this grant will attempt to understand the genetic and pathophysiological characteristics of this strong familial aggregation of morbid obesity by testing for genetic segregation of a major gene within these already ascertained families and by characterizing the clinical and biochemical traits of family members of the morbidly obese probands. Subsets may also be defined by the presence of conditions such as hypertension, hyperlipidemia, hyperinsulinemia, and diabetes, which are common in morbid obesity, but are not found in all such families. Biochemical and disease characterization in families may suggest mechanisms relating these disease conditions to morbid obesity and ultimately contribute to the early detection, control and prevention of obesity. Finally, white blood cells will be stored for future investigation of linkage of candidate DNA markers to morbid obesity.